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Opioids

1. NAME
   1.1 Substance
   1.2 Group
   1.3 Synonyms
   1.4 Identification numbers
      1.4.1 CAS number
      1.4.2 Other numbers
   1.5 Main brand names, main trade names
   1.6 Main manufacturers, main importers
2. SUMMARY
   2.1 Main risks and target organs
   2.2 Summary of clinical effects
   2.3 Diagnosis
   2.4 First aid measures and management principles
3. PHYSICOCHEMICAL PROPERTIES
   3.1 Origin of the substance
   3.2 Chemical structure
   3.3 Physical properties
      3.3.1 Colour
      3.3.2 State/form
      3.3.3 Description
   3.4 Other characteristics
      3.4.1 Shelf-life of the substance
      3.4.2 Storage conditions
4. USES
   4.1 Indications
      4.1.1 Indications
      4.1.2 Description
5. ROUTES OF EXPOSURE
   5.1 Oral
   5.2 Inhalation
   5.3 Dermal
   5.4 Eye
   5.5 Parenteral
   5.6 Other
6. KINETICS
   6.1 Absorption by route of exposure
   6.2 Distribution by route of exposure
   6.3 Biological half-life by route of exposure
   6.4 Metabolism
   6.5 Elimination and excretion
7. PHARMACOLOGY AND TOXICOLOGY
   7.1 Mode of action
      7.1.1 Toxicodynamics
      7.1.2 Pharmacodynamics
   7.2 Toxicity
      7.2.1 Human data
         7.2.1.1 Adults
         7.2.1.2 Children
      7.2.2 Relevant animal data
      7.2.3 Relevant in vitro data
   7.3 Carcinogenicity
   7.4 Teratogenicity
   7.5 Mutagenicity
   7.6 Interactions
   7.7 Main adverse effects
8. TOXICOLOGICAL ANALYSIS AND BIOMEDICAL INVESTIGATIONS
9. CLINICAL EFFECTS
   9.1 Acute poisoning
      9.1.1 Ingestion
      9.1.2 Inhalation
      9.1.3 Skin exposure
      9.1.4 Eye contact
      9.1.5 Parenteral exposure
      9.1.6 Other
   9.2 Chronic poisoning
      9.2.1 Ingestion
      9.2.2 Inhalation
      9.2.3 Skin exposure
      9.2.4 Eye contact
      9.2.5 Parenteral exposure
      9.2.6 Other
   9.3 Course, prognosis, cause of death
   9.4 Systematic description of clinical effects
      9.4.1 Cardiovascular
      9.4.2 Respiratory
      9.4.3 Neurological
         9.4.3.1 CNS
         9.4.3.2 Peripheral Nervous System
         9.4.3.3 Autonomic Nervous System
         9.4.3.4 Skeletal and smooth muscle
      9.4.4 Gastrointestinal
      9.4.5 Hepatic
      9.4.6 Urinary
         9.4.6.1 Renal
         9.4.6.2 Other
      9.4.7 Endocrine and Reproductive Systems
      9.4.8 Dermatological
      9.4.9 Eye, ear, nose, throat, local effects
      9.4.10 Haematological
      9.4.11 Immunological
      9.4.12 Metabolic
         9.4.12.1 Acid-Base Disturbance
         9.4.12.2 Fluid and electrolyte disturbances
         9.4.12.3 Others
      9.4.13 Allergic Reactions
      9.4.14 Other clinical effects
      9.4.15 Special risks
   9.5 Other
   9.6 Summary
10. MANAGEMENT
   10.1 General principles
   10.2 Life supportive procedures and symptomatic/specific treatment
   10.3 Decontamination
   10.4 Elimination
   10.5 Antidote treatment
      10.5.1 Adults
      10.5.2 Children
   10.6 Management discussion
11. ILLUSTRATITIVE CASES
   11.1 Case reports from literature
12. ADDITIONAL INFORMATION
   12.1 Specific preventive measures
   12.2 Other
13. REFERENCES
14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES)



    OPIOIDS

    International Programme on Chemical Safety
    Poisons Information Monograph (Group Monograph) G023
    Pharmaceutical

    This Monograph contains the following sections:
    1. Name, 2. Summary, 4. Uses, 7. Pharmacology and Toxicology,
    9.Clinical Effects, 10.Management.

    1.  NAME

        1.1  Substance

             Opioids

        1.2  Group

             Potent opioids: 
             Natural Opium
             Morphine 
             Diamorphine (Heroin) 
             Alphaprodine 
             Amileridine 
             Alfentanyl
             Fentanyl 
             Sufentanyl 
             Nalbuphine 
             Buprenorphine
             Butorphanol
             Dextromoramide 
             Dezocine 
             Ketobemidone
             Meptazinol
             Pentamorphone 
             Pentazocine
             Pethidine

             Less potent opioids: 
             Tincture Of Opium 
             Paregoric 
             Codeine 
             Hydromorphone
             Oxymorphone 
             Hydrocodone 
             Oxycodone
             Tramadol
             Dextropropoxyphene

             Others: 
             Diphenoxylate 
             Loperamide 
             Methadone

        1.3  Synonyms

             Pethidine: meperidine;

        1.4  Identification numbers

             1.4.1  CAS number

             1.4.2  Other numbers

                    ATC classification index:

                    Analgesics (N02) / Opioid (N02A)

        1.5  Main brand names, main trade names

        1.6  Main manufacturers, main importers

    2.  SUMMARY

        2.1  Main risks and target organs

             Opioid drugs produce their major effects on the Central
             Nervous System (CNS) and the bowel through mu receptors. In
             higher doses, they can interact with the other receptors.
             Main risks include:
             -  respiratory depression, coma, hypotension and
                non-cardiogenic pulmonary oedema.
             -  psychological or/and physical dependence.

        2.2  Summary of clinical effects

             Addicts use opioids for the excitement, euphoria,
             sensation of well-being and alteration of mood that they
             produce. The rapid onset of these effects with an intravenous
             bolus is called a "flash" or "rush".
             Opioids may cause nausea, vomiting, drowsiness, decreased gut
             motility, urinary retention, constipation, bradycardia,
             hallucinations, convulsions and coma. Hypotension can occur.
             Rhabdomyolysis with myoglobinuria and renal failure also
             occurs.
    
             Respiratory depression is common and may lead to cyanosis and
             respiratory arrest. In severe cases, there may be
             non-cardiogenic pulmonary oedema and cardiovascular
             collapse.
    
             Opioids usually produce pinpoint pupils, but they can be
             dilated if the patient is hypoxic.
    
             Dextropropoxyphene poisoning may also result in cardiac
             arrhythmias (including ventricular extrasystoles, bigeminy,
             ventricular tachycardia, ventricular fibrillation, heart

             block and sudden death). Serious effects usually occur within
             a few minutes of intravenous injection, and within an hour of
             oral ingestion, but can be delayed with methadone or
             slow-release preparations.

        2.3  Diagnosis

             The triad of coma, pinpoint pupils and depressed
             respirations strongly suggests opioid poisoning. The finding
             of needle tracks is suggestive of addiction, and further
             supports the diagnosis.

        2.4  First aid measures and management principles

             After ingestion of large doses and if the patient is
             conscious, consider administration of oral activated
             charcoal.
             In patients with severe respiratory depression, assisted
             ventilation and cardiovascular monitoring are required.
             Naloxone can be used as an antidote in severe poisoning and
             may be useful for the diagnosis in suspected opioid
             poisoning.

    3.  PHYSICOCHEMICAL PROPERTIES

        3.1  Origin of the substance

        3.2  Chemical structure

        3.3  Physical properties

             3.3.1  Colour

             3.3.2  State/form

             3.3.3  Description

        3.4  Other characteristics

             3.4.1  Shelf-life of the substance

             3.4.2  Storage conditions

    4.  USES

        4.1  Indications

             4.1.1  Indications

             4.1.2  Description

                    Their main use is in the treatment of
                    moderate-to-severe pain, but they are also used as
                    anti-diarrhoeal and anti-tussive agents.
    
                    Their ability to induce euphoria has led them to be
                    frequently abused, giving rise to psychological and
                    physical dependence.
    
                    (Reynolds, 1989).

    5.  ROUTES OF EXPOSURE

        5.1  Oral

        5.2  Inhalation

        5.3  Dermal

        5.4  Eye

        5.5  Parenteral

        5.6  Other

    6.  KINETICS

        6.1  Absorption by route of exposure

        6.2  Distribution by route of exposure

        6.3  Biological half-life by route of exposure

        6.4  Metabolism

        6.5  Elimination and excretion

    7.  PHARMACOLOGY AND TOXICOLOGY

        7.1  Mode of action

             7.1.1  Toxicodynamics

                    The acute toxic effects are an accentuation of
                    the pharmacodynamic effects.
                    Addicts use the opioids for the excitement, euphoria,
                    sensation of well-being and alteration of mood that
                    they produce. The rapid onset of these effects with an
                    intravenous bolus is called a "flash" or "rush".
                    Chronic effects include:

                    -  respiratory: acute pulmonary oedema may be due to a
                       direct toxic effect , as may be acute bronchospasm
                       (Oliver, 1986; Anderson, 1986; Conti et al., 1990;
                       Del Los Santos-Sastre, 1986)).
                    -  rhabdomyolysis: the commonly accepted explanation
                       is that it is due to compression of muscle during
                       prolonged coma aggravated by hypoxia, acidosis and
                       hypovolaemia. A direct effect has been suggested
                       (Conti et al., 1990; D'Agostino & Ernest, 1979;
                       Pearce & Cox, 1980).
                    -  renal. Renal damage may progress to terminal renal
                       insufficiency. Genetic factors (African Carribean),
                       and impurities in the opioids (especially if bought
                       on the street) have been suggested (Vassals &
                       Pezzano, 1987; Cunningham et al., 1980; Uzan et
                       al., 1988).
                    -  cutaneous. The effects may be systemic or local.
                       They may be due to adulterants, bacterial
                       contamination or direct effects of opioids (Louria
                       et al., 1967; Ellenhorn & Barceloux, 1988)..
                    -  immunological. Opioid addiction leads to reduced
                       resistance to cutaneous and respiratory
                       infections.
                    -  splenomegaly due to antigenic stimulation has been
                       described.

             7.1.2  Pharmacodynamics

                    Mu receptors were the first opioid-binding
                    sites described. Mu receptors are further classified
                    into mu1 and mu2 subclasses. Mu1 receptors have a high
                    affinity for morphine and are postulated to have
                    supraspinal analgesic properties. Stimulation of mu1
                    receptors causes almost none of the unwanted effects
                    of the opioids. Mu2 receptors have a lower affinity
                    for opioids than mu 1. Most of the adverse effects of
                    opioids can be attributed to stimulation of the mu2
                    receptors. These include respiratory depression,
                    delayed gastrointestinal motility, urinary retention,
                    bradycardia, miosis, euphoria and physical
                    dependence.
    
                    (Goodman et al., 1990).

        7.2  Toxicity

             7.2.1  Human data

                    7.2.1.1  Adults

                    7.2.1.2  Children

             7.2.2  Relevant animal data

             7.2.3  Relevant in vitro data

        7.3  Carcinogenicity

        7.4  Teratogenicity

        7.5  Mutagenicity

        7.6  Interactions

             The depressant effects of some opioids may be
             exaggerated and prolonged by phenothiazine, MAO inhibitors
             and tricyclic antidepressants.

        7.7  Main adverse effects

    8.  TOXICOLOGICAL ANALYSIS AND BIOMEDICAL INVESTIGATIONS

    9.  CLINICAL EFFECTS

        9.1  Acute poisoning

             9.1.1  Ingestion

                    Opioids may cause nausea, vomiting, drowsiness,
                    decreased gut motility, urinary retention,
                    constipation, bradycardia, hallucinations, confusion
                    and coma. Hypotension occurs occasionally.
                    Rhabdomyolysis may also occur.
                    Miosis is a characteristic (but not invariable) sign
                    of opioid poisoning.
                    Some opioids have a histamine-releasing effect which
                    can cause urticaria, pruritus, flushing and
                    hypotension. Such reactions may occur with therapeutic
                    doses.
                    Respiratory depression is common and may lead to
                    cyanosis and respiratory arrest. In severe cases,
                    there may be non-cardiogenic pulmonary oedema and
                    cardiovascular collapse.
                    Cardiac arrhythmias have been reported with
                    dextropropoxyphene.
                    Serious effects usually occur within an hour of oral
                    ingestion, but can be delayed with methadone or
                    slow-release preparations.
                    Acute poisoning may occur in "body-packers" after
                    leakage of contents.
    
                    (Conti et al., 1990)

             9.1.2  Inhalation

                    Acute poisoning has been described after
                    sniffing heroin ("chasing the dragon") (Conti et al.,
                    1990).

             9.1.3  Skin exposure

                    No data

             9.1.4  Eye contact

                    No data

             9.1.5  Parenteral exposure

                    The intravenous route is the preferred route in
                    the addict.
                    Acute poisoning has also been reported after
                    subcutaneous administration (Conti et a., 1990).
                    Opioids may cause nausea, vomiting, drowsiness,
                    decreased gut motility, urinary retention,
                    constipation, bradycardia, hallucinations, confusion
                    and coma when taken in overdose. Hypotension occurs
                    occasionally. Rhabdomyolysis may also occur.
                    Miosis is a characteristic sign of opioid
                    poisoning.
                    Some opiates have a histamine-releasing effect which
                    can cause a urticaria, pruritus, flushing and
                    hypotension. Such reaction may occur with therapeutic
                    doses.
                    Respiratory depression is common and may lead to
                    respiratory arrest. In severe cases there may be a
                    non-cardiogenic pulmonary oedema and cardiovascular
                    collapse.

             9.1.6  Other

                    No data

        9.2  Chronic poisoning

             9.2.1  Ingestion

                    Dependence has been described.

             9.2.2  Inhalation

                    Dependence has been described. Spongiform
                    leuco-encephalitis may occur with heroin.

             9.2.3  Skin exposure

                    No data

             9.2.4  Eye contact

                    No data

             9.2.5  Parenteral exposure

                    The primary risks of chronic intoxication in
                    drug abusers are physical and psychological
                    dependence, systemic complications due to opioids,
                    adulterants and multiple drug abuse, and infectious
                    complications, particularly AIDS and hepatitis B and
                    C.

             9.2.6  Other

                    No data

        9.3  Course, prognosis, cause of death

             If treatment is rapidly instituted, the outcome is
             generally good (Conti et al., 1990; Larpin et al., 1990).
             Complications include:
             -  aspiration pneumonia which may be severe,
             -  haemodynamic disturbances (bradycardia, hypotension and
                vasovagal collapse),
             -  hypothermia,
             -  rhabdomyolysis
             -  non cardiac pulmonary oedema,
             -  convulsions (due to impurities in «street drugs»)
             -  hypoxic brain damage.
             Death can result from prolonged apnoea or a hypersensitivity
             reaction.

        9.4  Systematic description of clinical effects

             9.4.1  Cardiovascular

             9.4.2  Respiratory

             9.4.3  Neurological

                    9.4.3.1  CNS

                    9.4.3.2  Peripheral Nervous System

                    9.4.3.3  Autonomic Nervous System

                    9.4.3.4  Skeletal and smooth muscle

             9.4.4  Gastrointestinal

             9.4.5  Hepatic

             9.4.6  Urinary

                    9.4.6.1  Renal

                    9.4.6.2  Other

             9.4.7  Endocrine and Reproductive Systems

             9.4.8  Dermatological

             9.4.9  Eye, ear, nose, throat, local effects

             9.4.10 Haematological

             9.4.11 Immunological

             9.4.12 Metabolic

                    9.4.12.1 Acid-Base Disturbance

                    9.4.12.2 Fluid and electrolyte disturbances

                    9.4.12.3 Others

             9.4.13 Allergic Reactions

             9.4.14 Other clinical effects

             9.4.15 Special risks

        9.5  Other

        9.6  Summary

    10. MANAGEMENT

        10.1 General principles

             Rapidly assess the vital signs.
             Maintain an airway.
             Assure ventilation (there is a danger of underestimating the
             severity of respiratory depression).
             Administer oxygen by nasal cannulae, face mask, or
             endotracheal tube.
             Ensure intravenous access.
             Infuse isotonic glucose solution.
             Monitor the electrocardiogram.
             Overenthusiastic administration of the specific antidote
             naloxone can provoke acute withdrawal in those habituated to
             opioids, and this can complicate treatment. Naloxone is a
             competitive antagonist. It is relatively ineffective in
             treating poisoning by partial agonists, particularly
             buprenorphine.
             Careful titration of the dose of antidote administered should
             allow the treatment of respiratory depression (assuring a
             respiratory rate above 14 breaths per minute) without
             provoking acute withdrawal.

             Decontamination if indicated (for example, with
             body-packers).

        10.2 Life supportive procedures and symptomatic/specific treatment

             Standard treatment of opioid overdose is (Baud & Bismuth,
             1987):
             -  artificial ventilation or mask ventilation
             -  use of naloxone
             Failure to regain consciousness requires consideration of
             prolonged cerebral anoxia or poisoning by other psychotropic
             drugs.
    
             Treatment of a complicated opioid overdose may require:
             -  infusion of plasma expanders for cardiovascular collapse
                unresponsive to naloxone. Pressor amines may also be used.
                If there is no response, then measurement of CVP, and
                pulmonary artery catheterization allow more precise
                haemodynamic treatment. Hyperdynamic circulation and
                increased cardiac output and a fall in peripheral
                resistance and a slight increase in heart rate may appear
                if fluids are given to preserve renal function.
             -  mechanical ventilation with PEEP is the preferred
                treatment of non cardiac pulmonary oedema which usually
                responds rapidly. Ventilation may be stopped after 2 to 4
                days. It may also be required for hypoxemia.
             -  diazepam is used to control convulsions
             -  other measures may be required to treat pulmonary
                aspiration, rhabdomyolysis, or hyperthermia.
    
             Dextropropoxyphene: ECG monitoring is advised for at least
             8 hours following dextropropoxyphene exposure. Cardiac
             arrhythmias should be treated with either phenytoin or
             atenolol. Disopyramide, lignocaine, procainamide, quinidine
             and atropine are all contra-indicated since they may
             exacerbate the conduction defects.
    
             Treatment of withdrawal syndrome in opioid abuser:
             The management of the withdrawal syndrome should not be
             exclusively pharmacological in nature but should include a
             full evaluation of the patient to determine the most
             appropriate approach to therapy.  One of two general
             approaches is commonly adopted.  The first comprises
             substitution of the drug with a longer-acting opioid, such as
             methadone, followed by a gradual reduction in dosage of the
             substitute drug. The second comprises use of various
             pharmacological agents, such as clonidine and/or a
             benzodiazapine, which will mitigate symptoms and signs of
             withdrawal. Psychological support may be necessary. Indeed,
             some schools of thought contend that psycho-social support
             alone is the only effective treatment for opioid withdrawal
             states.
    

             When clonidine is employed, the dose is 0.006 mg/kg/day, in
             divided doses, adjusted as necessary according to withdrawal
             symptoms and clonidine side-effects (such as sedation and/or
             postural hypotension). The dosage of clonidine should then be
             gradually reduced, typically over a one- to two-week
             period.
    
             If symptoms and signs of opioid withdrawal do not respond to
             the use of clonidine and/or benzodiazepines, then the use of
             propantheline (for stomach cramps) or atropine (for
             diarrhoea) may be considered.
    
             Opioid-dependent individuals with co-existent medical or
             surgical conditions requiring pain relief should receive
             conventional treatment, including if necessary the
             administration of opioids.
             Substitution is preferred to drug withdrawal during
             pregnancy.
             (Ellenhorn & Barceloux, 1988, Goodman et al., 1990).
    
             Acute withdrawal in the neonate can be treated with dilute
             morphine solution (Paregoric elixir-400 micrograms morphine
             per mL), 0.2 mL every 3 to 4 hours as needed to relieve
             symptoms without causing sedation. If there is no response,
             the dose can be increased in steps of 0.1 mL (0.04 mg
             morphine) (Goldfrank & Bresnitz, 1990). Diazepam,
             chlorpromazine and phenobarbitone may be required as
             sedatives for several days or weeks.

        10.3 Decontamination

             In the case of ingestion of large doses of opioids,
             oral activated charcoal can be recommended.
             If there is a suspicion that the patient is a body packer,
             then the following are required:
             -  rectal (and vaginal) examination and plain erect and
                supine abdominal X-rays. Examination of the colon with
                water soluble contrast medium, sigmoidoscopy, enema, and
                stool examination for several days, may all be needed
                (Karhunen et al., 1987; Marc et al., 1989).
             Packets in the stomach cannot be removed by gastric lavage.
             Induced emesis should be avoided. Close monitoring is
             required because of the high risk of rupture of the packets
             
             -  foreign objects in the gastro-intestinal tract may require
                whole bowel irrigation with polyethylene glycol solution
                with stool examination. Surgery may be indicated for
                mechanical obstruction or if there is evidence of packet
                rupture.

        10.4 Elimination

             Haemodialysis, haemoperfusion and peritoneal dialysis
             are not recommended (Ellenhorn & Barceloux, 1988).

        10.5 Antidote treatment

             10.5.1 Adults

                    Naloxone is a specific competitive antagonist.
                    It can be administered by intravenous (IV) bolus, IV
                    infusion or intramuscular (IM) routes. Adverse effects
                    and problems include:
                    -  a short duration of action (10 to 45 minutes)
                       compared with that of opioids; symptoms of
                       poisoning can reappear after the initial injection,
                       with consequent risk of respiratory depression and
                       apnoea, necessitating repeat administration.
                    -  an acute withdrawal syndrome may appear a few
                       minutes after the injection, peaking at 30
                       minutes
                    -  there is a risk of rebound sympathetic activity,
                       with acute pulmonary oedema and cardiac
                       arrhythmia.
    
                    (Buad & Bismuth, 1987; Ellenhorn & Barceloux, 1988;
                    Goodman et al., 1990).
    
                    1) Slow administration of an initial intravenous dose
                    of 0.4 to 2 mg in adults, titrated until the
                    respiratory rate is above 14 breaths per minutes, but
                    without provoking signs of acute withdrawal. If the
                    initial dose has no effect, it can be repeated after 2
                    or 3 minutes.
    
                    2) Maintenance treatment, which may be needed because
                    of the short duration of action of naloxone, is given
                    by infusing 1.6 to 2.4 mg naloxone in isotonic (5%)
                    glucose solution, or by syringe pump, at a rate
                    sufficient to maintain the respiratory rate above 14
                    breaths per minute (usually 0.4 to 0.8 mg per hour).
                    This is especially important if large doses of
                    slow-release preparations or longer-acting agents
                    (such as methadone)have been taken. If artificial
                    ventilation is required because of respiratory
                    insufficiency or pulmonary oedema, then naloxone
                    should be stopped.

             10.5.2 Children

                    The initial dose in children is 10 to 30
                    microgram per kg, followed by a dose of 100 microg per
                    kilogram if there is no response. Infusion should be

                    at a rate of 30 microg per kg per hour. Infusion may
                    be recommended in the case of opioids with a long
                    half-life (e.g. methadone, dextropropoxyphene and
                    buprenorphine).

        10.6 Management discussion

    11. ILLUSTRATITIVE CASES

        11.1 Case reports from literature

    12. ADDITIONAL INFORMATION

        12.1 Specific preventive measures

        12.2 Other

    13. REFERENCES

        Anderson K (1986) Bronchospam and intravenous street heroin.
        Lancet, 1: 1208
    
        Baud FJ & Bismuth C (1987) Traitement d'urgence de l'overdose. Rev
        Prat, 37: 1723-1727
    
        Cunningham EE, Brentjens JR, Zielezny MA, Andres GA, Venuto RC
        (1980) Heroin nephropathy. A clinicopathologic and epidemiologic
        study. Am J Med, 68: 47-53
    
        D'Agostino RS & Ernest NA (1979) Acute myoglobinuria and heroin
        snorting. JAMA, 241: 277
    
        Del Los Santos-Sastre S, Capote-Gil F, Gonzales-Castro A (1986)
        Airway obstruction and heroin inhaling. Lancet, 2: 1158
    
        Ellenhorn MJ & Barceloux DG (1988). Medical toxicology. Diagnosis
        and treatment of human poisoning. New York, Elsevier, 698-709
    
        Goldfrank LR & Bresnitz EA (1990). Opioids. In: Goldfrank LR,
        Toxicologic Emergencies, 4th ed, East Norwalk, Appleton & Lange,
        433-445
    
        Goodman, Gilman A, Rall TW, Nies AS, Taylor P (1990). Goodman and
        Gilman's The pharmacological basis of therapeutics, 8th ed,
        New-York, Pergamon Press, 489-504
    
        Karhunen  PJ, Penttilä A, Panula A (1987) Detection of heroin
        "body-packers" at Helsinski airport. Lancet, 1: 1265
    
        Larpin R, Vincent A, Perret C (1990) Morbidite et mortalite
        hospitalières de l'intoxication aiguë par les opiaces. Presse Med,
        19: 1403-1406
    

        Louria DB, Hensle T, Rose J (1967) The major medical complications
        of heroin addiction. Ann Intern Med, 67: 1-22
    
        Marc B, Gherardi R, Baud F, Cattin JM, Garnier R, Diamant-Berger O
        (1989). Transport in corpore de stupefiants: diagnostic et
        traitement medical. Encyclop Med Chir - Instant Med, 17-20
    
        Oliver RM (1986) Bronchospasm and heroin inhalation. Lancet, 1:
        915
    
        Pearce CJ & Cox JGC (1980) Heroin and hyperkalaemia. Lancet, 2:
        923
    
        Uzan M, Volochine L, Rondeau E, Viron B, Mougenot B, Beaufils H,
        Pourriat JL, Chauveau P (1988) Les atteintes renales associees à
        l'abus d'heroïne. Nephrologie, 9: 217-221
    
        Vassals T & Pezzano M (1987) Les complications medicales de
        l'heroinomanie. Rev Prat, 37: 1729-1734

    14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE 
        ADDRESS(ES)

        Author:     Medical Toxicology Unit, 
                    Guy's and St Thomas' Trust
                    Avonley Road, London SE14 5ER, UK
    
        Date:       August, 1996
    
        Reviewers:  R Ferner, M Mathieu-Nolf, MO Rambourg Schepens
                    (coordinator)
                    London, March, 1998
    
        Editor:     Dr M.Ruse (IPCS, February, 1999)
    





See Also:
        Opioid analgesics (UK PID)